Process and intermediates to prepare latanoprost

ABSTRACT

The present invention is a novel intermediate, compound of the formula (VI)                    
     and salts thereof. In addition, the invention includes a process for the preparation of a 15(S)-prostaglandin intermediates compounds (IV) and (XVIII) which comprises (1) contacting a the corresponding enone with (−)-chlorodiisopinocampheylborane while maintaining the reaction mixture temperature in the range of from about −50° to about 0° and (2) contacting the reaction mixture of step (1) with a boron complexing agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application claims priority of invention under 35 U.S.C.§119(e) from U.S. provisional patent application Serial No. 60/306,026,filed Jul. 17, 2001.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is a process, including intermediates, to producelatanoprost, a pharmaceutical agent useful in treating ophthalmicconditions.

2. Description of the Related Art

U.S. Pat. No. 5,422,368 discloses latanoprost (Example 2) and itsusefulness as an ophthalmic agent. The patent discloses a process(Example 2) to prepare latanoprost and two closely related compounds.

There are very limited numbers of examples of reductions ofα,β-unsaturated enones with chlorodiisopinocampheylborane. J. Am. Chem.Soc., 110(5), 1539-46 (1988) describes a single example of reduction ofan acyclic aryl enone, 4-phenyl-3-buten-2-one, withchlorodiisopinocampheylborane giving an 81% eantiomeric selectivity, andno examples of simple acyclic non-aryl conjugated enones.

Bull. Korean Chem. Soc., 15(12), 1033-4 (1994) addresses the issue of1,2 versus 1,4 reduction with chlorodiisopinocampheylborane but did notdiscuss the enantioselectivity or diastereoselectivity of thereductions.

Tetrahedron Letters 1067-1070 (1976) discloses a cyclopentane diol-acidwhere the side-chain did not contain any aromatic functionality.

SUMMARY OF INVENTION

Disclosed is a compound of the formula (VI)

where:

(1) R₃ is —H and R₄ is —H,

(2) R₃ is —H and R₄ is —O—CH₃ and

(3) R₃ and R₄ are taken together to form a five member ring attached tothe 3- and 4-positions of the phenyl ring where the second ring from theR₃-position to the R₄-position is —CH═CH—O— and

where . . . is a single or double bond and pharmaceutically acceptablesalts thereof.

Also disclosed is a process for the preparation of a 15(S)-prostaglandinintermediate selected from the group consisting of compound (IV)

where R₃, R₄ and . . . are as defined above and where X₁₁ is phenyl orphenyl substituted with one thru three C₁-C₄ alkyl, one thru three C₁-C₄alkoxy, one phenyl, one thru three —F, —Cl, —Br and —I and compound(XVIII)

where X₁₁ is defined above which comprises:

(1) contacting a compound selected from the group consisting of compound(III)

where R₃, R₄, X₁₁ and . . . are as defined above or compound (XVII),respectively,

where X₁₁ is defined above with (−)-chlorodiisopinocampheylborane whilemaintaining the reaction mixture temperature in the range of from about−50° to about 0° and

(2) contacting the reaction mixture of step (1) with a boron complexingagent.

DETAILED DESCRIPTION OF THE INVENTION

Latanoprost (XVI) is known, see U.S. Pat. No. 5,422,368, Example 2.

The process of the present invention is set fort in CHARTs A and B andin EXAMPLES 1-12.

The enone (III), as well as the other compounds of the invention, hasthree possibilities for the substitution on the phenyl ring of thebottom side chain. These are where R₃ and R₄ are:

(1) R₃ is —H and R₄ is —H which gives phenyl,

(2) R₃ is —H and R₄ is —O—CH₃ which give 4-methoxyphenyl and

(3) R₃ and R₄ are taken together to form a five member ring attached tothe 3- and 4-positions of the phenyl ring where the second ring from theR₃-position to the R₄-position is —CH═CH—O—;

where . . . is a single or double bond and

where X₁₁ is phenyl or phenyl substituted with one thru three C₁-C₄alkyl, one thru three C₁-C₄ alkoxy, one phenyl, one thru three —F, —Cland —Br. It is preferred that R₃ and R₄ are both —H. It is preferredthat X₁₁ is phenyl.

The enone (III) must be protected at the C-11 position as is known tothose skilled in the art. It is preferred that for the protecting group—CO—X₁₁, X₁₁ is phenyl or phenyl substituted with one thru three C₁-C₄alkyl, one thru three C₁-C₄ alkoxy, one phenyl, one thru three —F, —Cland —Br. With regard to the (−)-chlorodiisopinocampheylborane reductionof the α,β-unsaturated enone (III) the reduction can be performed in anychemically inert solvent that adequately dissolves the enone (III).Suitable solvents include THF, methylene chloride and DME and mixturesthereof. MTBE and toluene alone are not operable. The use of acosolvent, such as hexane, heptane, isooctane or similar hydrocarbons isnot necessary but is preferred. This is important since(−)-chlorodiisopinocampheylborane is available commercially as asolution in these solvents. MTBE and toluene can be used as thecosolvent. The nature of the solvent has virtually no effect with regardto the 15(S)/15(R) ratio in the product. It is preferred that from about3 to about 4 equivalents of (−)-chlorodiisopinocampheylborane be used;it is more preferred that at least 3.5 equivalents of(−)-chlorodiisopinocampheylborane be used. With fewer equivalents thereaction is incomplete; there is no improvement in rate or selectivitywith more equivalents. When the (−)-chlorodiisopinocampheylborane iscontacted with the α,β-unsaturated enone (III), the temperature shouldbe maintained less than 0°. It is preferred that the temperature bemaintained at less than −20°; it is more preferred that the temperaturebe maintained in the range of from about −35 to about −45°. Above −35°the selectivity decreases and below about −45° the rate becomes too slowto be practical.

When the reaction is complete, the excess(−)-chlorodiisopinocampheylborane must be destroyed by use of a boroncomplexing agent which is selected from the group consisting of water,C₁-C₆ alcohols and diols, ethanolamine, diethanolamine, triethanolamineand mixtures thereof. It is preferred that the boron complexing agent begroup be water and diethanolamine; it is more preferred that thecomplexing agent be water.

It is preferred that prior to step (2), the reaction mixture of step (1)is contacted with a readily reducible aldehyde or ketone. It ispreferred that the readily reducible aldehyde or ketone is selected fromthe group consisting of C₁-C₆ aldehydes and ketones and benzaldehyde; itis more preferred that the readily reducible aldehyde or ketone isacetone or methylethylketone. When adding the boron complexing agent itis preferred that a base also be added. It is preferred that the base isselected from the group consisting of carbonate, bicarbonate, mono- di-and tri-C₁-C₆ alkylamines, pyridine and pyridine substituted with C₁-C₄alkyl; it is more preferred that the base be bicarbonate or carbonate.It is even more preferred that the base be bicarbonate.

Either prior to, or after, step (2), it is preferred to warm thereaction mixture to about 15 to about 25°. It is preferred that thereaction mixture is warmed from about 1 to about 3 hr.

Latanoprost (XVI) is known to be useful as an ophthalmic pharmaceuticalagent, see U.S. Pat. Nos. 5,296,504 and 5,422,368. In addition,International Publication WO98/30900 discloses that latanoprost (XVI) isuseful in treating another ophthalmic condition, myopia.

The process of CHART B (and EXAMPLEs 11 & 12) starts with a known enone(XVII) and transforms it to the 15-alcohol (XVIII) intermediate known tobe useful in the production of pharmaceutically useful prostaglandins,see Tetrahedron Letters, 1076-1070 (1976) and J. Am. Chem. Soc. 92,397-8 (1970). The process of the reduction of the non-arylα,β-unsaturated ketone (XVII) is analogous to the reduction of the arylα,β-unsaturated ketone (III).

The products where R₃ is —H and R₄ is —O—CH₃ and where R₃ and R₄ aretaken together to form a five member ring attached to the 3- and4-positions of the phenyl ring where the second ring from theR₃-position to the R₄-position is —CH—CH—O— are also known to be usefulpharmaceutical agents. Those two agents can also be prepared by theprocess of the present invention.

Definitions and Conventions

The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

Definitions

All temperatures are in degrees Celsius.

Latanoprost (XVI) refers to(5Z)-(9CI)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoicacid 1-methylethyl ester. It is also known as17-phenyl-18,19,20-trinor-PF_(2α) isopropyl ester.

MTBE refers to methyl t-butyl ether.

TLC refers to thin-layer chromatography.

THF refers to tetrahydrofuran.

THP refers to tetrahydropyranyl.

Saline refers to an aqueous saturated sodium chloride solution.

Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support, eluent). Itis understood that the appropriate fractions are pooled and concentratedto give the desired compound(s).

CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts arereported in ppm (δ) downfield from TMS.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemicalshifts are reported in ppm (δ) downfield from tetramethylsilane.

TMS refers to trimethylsilyl.

−φ refers to phenyl (C₆H₅).

MS refers to mass spectrometry expressed as m/e, m/z or mass/chargeunit. [M+H]⁺ refers to the positive ion of a parent plus a hydrogenatom. EI refers to electron impact. CI refers to chemical ionization.FAB refers to fast atom bombardment.

HRMS refers to high resolution mass spectrometry.

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance and bioavailability.

psi refers to pounds per square inch.

When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v).

When the solubility of a solid in a solvent is used the ratio of thesolid to the solvent is weight/volume (wt/v).

DIBAL refers to diisobutyl aluminum hydride.

THAM refers to tris(hydroxymethyl)aminomethane.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following detailed examples describe how toprepare the various compounds and/or perform the various processes ofthe invention and are to be construed as merely illustrative, and notlimitations of the preceding disclosure in any way whatsoever. Thoseskilled in the art will promptly recognize appropriate variations fromthe procedures both as to reactants and as to reaction conditions andtechniques.

Preparation 1

Potassium 5-(triphenylphosphoranylidene)pentaonate

4-Carboxybutyltriphenylphosphonium bromide (2.91 g) is stirred with THF(10 mL) and the slurry cooled to 0°. Potassium t-butoxide (20% w/v, 7.6mL) solution in THF is cooled to 0°. The butoxide solution is added tothe slurry dropwise maintaining the temperature at 0 to 5° and thenstirring for 1 hour. The resulting ylide solution is then cooled to−10°.

Example 1[3aR-[3aα,4α(E),5β,6aα]]-5-(benzoyloxy)hexahydro-4-(3-oxo-5-phenyl-1-pentenyl)-2H-cyclopenta[b]furan-2-one(III)

Lithium chloride (2.6 g) is dissolved in THF (170 mL). Dimethyl(2-oxo-4-phenylbutyl)phosphonate (II, 7.87 g) and triethylamine (4.3 mL)are added. The mixture is stirred and cooled to −10°. A solution of theCorey aldehyde benzoate,(1S,5R,6R,7R)-6-formyl-7-(benzyloxy)-2-oxabicyclo[3.3.0]octan-3-one (I,8.42 g) in THF (75 mL) is added to the reaction mixture over threehours. The resulting mixture is stirred for 18 hours at −10°. At the endof this time, MTBE (100 mL) is added and the mixture warmed to 0 to+20°. Sodium bisulfite (38%, 100 mL) is added and the two-phase mixturewas stirred for 10 min. The phases are separated and the organic phaseis washed with saturated aqueous sodium bicarbonate solution (100 mL).The organic phase is separated and concentrated under reduced pressureto a volume of <100 mL. Ethyl acetate (200 mL) is added and the mixtureis concentrated to a volume of 50 mL. MTBE (100 mL) is added and themixture is allowed to cool to 20-25 deg for 1 hour. The mixture is thencooled to −20° for 2 hours. The solids were filtered, washed with MTBEand dried on a nitrogen press to give the title compound, mp=117-118°;NMR (CDCl₃, 400 MHz) δ 7.82, 7.41, 7.28, 7.10, 7.02, 6.49, 6.04, 5.12,4.91, 2.72 and 2.5-2.1; CMR (CDCl₃, 100.6 MHz) δ 198.5, 175.7, 165.8,143.0, 140.8, 133.5, 131.4, 129.4, 128.5, 126.2, 83.0, 78.4, 54.0, 42.5,37.8, 34.8 and 29.9.

Example 2[3aR-[3aα,4a(1E,3S*),5β,6aα]]-5-(Benzoyloxy)hexahydro-4-(3-hydroxy-5-phenyl-1-pentenyl)-2H-cyclopenta[b]furan-2-one(IV)

A mixture of[3aR-[3aα,4α(E),5β,6aβ]]-5-(benzoyloxy)hexahydro-4-(3-oxo-5-phenyl-1-pentenyl)-2H-cyclopenta[b]furan-2-one(III, EXAMPLE 1, 10.0 g, 0.0247 mole) in THF (100 mL) is cooled to −38to −42°. A solution of (−)-chlorodiisopinocampheylborane (2M in hexane;43 mL) is added to the enone (III) mixture maintaining the internaltemperature at less than −35°. When the addition is complete, themixture is stirred at −38 to −42° for 18 hours. At this time acetone(12.7 mL) is added and the mixture is allowed to warm to 20-25° andstirred for two hours. MTBE (100 mL) is added and then a solution ofsodium bicarbonate (10 g) in water (150 mL) is added. The two phasemixture is stirred for 15 min. The phases are separated and the organicphase is washed with water (100 mL). The organic phase is concentratedunder reduced pressure. MTBE (300 mL) is added and the mixture thenconcentrated. Acetonitrile (100 mL) is added and the mixture is againconcentrated. Acetonitrile (150 mL) and heptane (100 mL) are added. Thetwo-phase mixture is stirred for 5 min and then allowed to settle. Thephases are separated. The acetonitrile phase is extracted with heptane(3×100 mL). The acetonitrile phase is concentrated. A portion of theconcentrate is removed and purified by chromatography (silica gel,230-400 mesh; heptane/ethyl acetate, 1/1) to give the title compound,mp=78-81°; NMR (CDCl₃, 400 MHz) δ 7.77, 7.32, 7.19, 7.04, 6.94, 5.45,5.37, 5.01, 4.79, 3.88, 2.61-2.23, 2.01 and 1.60; CMR (CDCl₃, 100.6 MHz)δ 176.5, 166.0, 141.7, 136.0, 133.3, 129.5, 128.4, 125.8, 83.3, 79.2,71.2, 53.9, 42.6, 38.7, 37.5, 34.9 and 31.5.

Example 3[3aR-[3aα,4a(1E,3S*),5β,6aα]]-5-(Benzoyloxy)hexahydro-4-(3-hydroxy-5-phenyl-1-pentyl)-2H-cyclopenta[b]furan-2-one(V)

[3aR-[3aα,4a(1E,3S*),5β,6aα]]-5-(benzoyloxy)hexahydro-4-(3-hydroxy-5-phenyl-1-pentenyl)-2H-cyclopenta[b]furan-2-one(IV, EXAMPLE 2) is dissolved in THF (125 mL). Platinum on carboncatalyst (5%, 1 g) and triethylamine (3.4 mL) are added. The mixture ispurged with nitrogen and then and the mixture is stirred vigorouslyunder 5 psi hydrogen at 20°±5°. When the reaction was complete asmeasured by HPLC, the reaction is purged with nitrogen. The mixture isfiltered over celite. The filtrate is concentrated under reducedpressure to give the crude product. A portion of the product is removedand purified by chromatography (silica gel, 230-400 mesh; heptane/ethylacetate, 1/1) to give the title compound, mp=68-70°; NMR (CDCl₃, 400MHz) δ 7.91, 7.47, 7.36, 7.19, 7.10, 5.18, 4.99, 3.56, 2.84-2.57,2.44-2.26, 1.71-1.16; CMR (CDCl₃, 100.6 MHz) δ 176.9, 166.0, 141.8,133.2, 129.6, 128.4, 125.9, 84.4, 80.1, 70.8, 52.6, 43.5, 39.0, 37.7,36.2, 35.1, 32.0 and 29.5; MS calculated m/z=408, found m/z=409 (m+1).

Example 4 2-[(1R, 2R, 3R,5S)-3,5-Dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]aceticAcid (VI)

A mixture of potassium hydroxide (10) in methanol (300 ml) and water (5mL) is added to[3aR-[3aα,4a(1E,3S*),5β,6aα]]-5-(benzoyloxy)hexahydro-4-(3-hydroxy-5-phenyl-1-pentyl)-2H-cyclopenta[b]furan-2-one(V, EXAMPLE 3). The mixture is stirred and heated in an 80° oil bath forabout 2 hours. When the reaction is complete, the mixture isconcentrated under reduced pressure. Water (100 mL) and MTBE (100 mL)are added and the mixture stirred at 20-25° for 15 min. The phases areallowed to separate. The product is in the aqueous phase and the organicphase is removed and discarded. The pH of the aqueous phase is adjustedto 1 to 1.5 by the addition of hydrochloric acid (3 N, about 60 mL arerequired). The solution is stirred at 20-25°. After 30 min, MTBE (100mL) is added and the mixture stirred at 20-25° for about 12 hours. Thephases are separated and the aqueous phase extracted once with MTBE (50mL). The MTBE phases are combined and washed with sodium carbonate (1 N,50 mL). The MTBE mixture is stirred with a solution of potassiumhydroxide (2.8 g, 42.5 mmole) in water (100 mL) for 30 min. The phasesare separated and the aqueous phase is added to a slurry of citric acidmonohydrate (8.90 g) and ethyl acetate (100 mL) at 20-25 deg. Themixture is stirred for 15 min and the phases are separated. The aqueousphase is extracted with ethyl acetate (5×50 mL). The combined organicphases are dried over anhydrous sodium sulfate (8.90 g) for 15 min. Theethyl acetate extract is concentrated under reduced pressure to a volumeof 100 mL maintaining the internal temperature less than 300. Ethylacetate (200 mL) is added and the mixture is again concentrated to avolume of 100 mL. The resulting slurry is stirred at 0-5° for 30 min.The solids are filtered and washed with heptane/ethyl acetate (1/1, 35mL), then dried on a nitrogen press to give the title compound.

Example 5[3aR-[3aα,4α(R*),5β,6aα]]-Hexahydro-5-hydroxy-4-(3-hydroxy-5-phenylpentyl)-2H-cyclopenta[b]furan-2-one(VII)

2-[(1R, 2R, 3R,5S)-3,5-Dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]aceticacid (VI, EXAMPLE 4, 4.80 g) and toluene (100 mL) are stirred and theslurry heated to reflux for 30 min. After 30 min, the toluene is slowlydistilled at atmospheric pressure to remove water. After about 1 hour ofdistillation, all the hydroxy acid has dissolved. The solution is thendistilled to a volume of about 50 mL. The mixture is then cooled toabout 800 and ethyl acetate (25 mL) is added. The mixture is then cooledto about 30° and heptane (20 mL) is added. The mixture is seeded with asmall amount of the title compound. The mixture is stirred at about 30°for 10 min, during which time massive crystallization occurred. Afterthe product had crystallized, heptane (30 mL) is added over 15 min. Theslurry is cooled to 20-25° and stirred for 1 hour. The product isfiltered and dried under nitrogen to give the title compound, mp=69-71°;NMR (CDCl_(3, 400) MHz) δ 7.35, 7.26, 5.00, 4.06, 3.68, 2.89-2.55,2.34-2.07 and 1.87-1.34; CMR (CDCl₃, 100.6 MHz) δ 177.8, 141.9, 128.4,125.9, 84.0, 71.2, 53.9, 43.1, 41.4, 39.1, 36.0, 35.2, 32.0 and 28.9.

Example 6(3aR,4R,5R,6aS)-5-(1-Ethoxyethoxy)-4-[(3R)-3-(1-ethoxyethoxy)-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-one(X)

[3aR-[3aα,4α(R*),5β,6aα]]-Hexahydro-5-hydroxy-4-(3-hydroxy-5-phenylpentyl)-2H-cyclopenta[b]furan-2-one(VII, EXAMPLE 5, 1.0 g, 3.3 mmoles) is dissolved in methylene chloride(3 mL) and the mixture is placed in a sealable pressure tube. Add 1.0 mLof a mixture of trichloracetic acid (0.27 g) in methylene chloride (10mL) followed by ethyl vinyl ether (6.3 mL). The pressure tube is closedand heated to 45° in an oil bath for about 8 hours. At this time,triethylamine (0.12 mL) is added and the mixture is stirred for 10minutes. The mixture is then concentrated under reduced pressure.

Example 7(3aR,4R,5R,6aS)-5-(1-Ethoxyethoxy)-4-[(3R)-3-(1-ethoxyethoxy)-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-ol(XI)

(3aR,4R,5R,6aS)-5-(1-Ethoxyethoxy)-4-[(3R)-3-(1-ethoxyethoxy)-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-one(X, EXAMPLE 6) is dissolved in THF (14 mL) and the mixture cooled to−40°. Using a syringe pump, DIBAL (1.0 M, 3.78 mL in toluene) is addedover 15 minutes, maintaining the internal temperature at less than −30°.The mixture is stirred for 15 minutes after the completion of theaddition, then ethyl acetate (0.38 mL) is added. The mixture is pouredinto a solution of potassium sodium tartarate (10 g in 30 mL of water)and warmed to 20-25°. The two phase mixture is heated to 45° for 1 hrand then cooled. The phases are separated and the organic phase isconcentrated.

Example 87-[(1R,2R,3R,5S)-3-(1-Ethoxyethoxy)-5-hydroxy-2-[(3R)-3-(1-ethoxyethoxy)-5-phenylpentyl]cyclopentyl-5-heptenoicAcid (XII)

(3aR,4R,5R,6aS)-5-(1-Ethoxyethoxy)-4-[(3R)-3-(1-ethoxyethoxy)-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-ol(XI, EXAMPLE 7) is dissolved in dry THF (10 mL) and added to a mixturecontaining potassium 5-(triphenylphosphoranylidene)pentaonate(PREPARATION 1) solution at −10° to −5°. The resulting mixture isstirred for about 3 hours at less than −5°. Water (30 mL; 0°) is addedover 10 minutes, then ethyl acetate (20 mL) and aqueous THAM solution(10 mL) is added. The phases are separated and the organic phase iswashed with aqueous THAM solution (15%, 2×15 mL). The aqueous phases arecombined and washed once with ethyl acetate (15 mL). MTBE (50 mL) isadded to the combined aqueous phases. The mixture is acidified to pH=3with aqueous phosphoric acid (40%). The organic phase is separated andconcentrated under reduced pressure to 20 mL. Solids(5-diphenypphosphinopentanoic acid) crystallized. MTBE (50 mL) is addedand the slurry concentrated under reduced pressure to a volume of 20 mL.The solid is filtered and washed with MTBE (100 mL). The filtrate isconcentrated under reduced pressure to give the title compound.

Example 9 Latanoprost Acid;(5Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]5-heptenoicAcid (XV)

7-[(1R,2R,3R,5S)-3-(1-Ethoxyethoxy)-5-hydroxy-2-[(3R)-3-(1-ethoxyethoxy)-5-phenylpentyl]cyclopentyl-5-heptenoicacid (XII, EXAMPLE 8) is dissolved in THF (30 mL). Water (15 mL) andphosphoric acid (85 wt %; 0.67 mL) are added and the mixture is heatedto reflux for about 2 hours. The mixture is cooled and MTBE (30 mL) isadded. The phases are separated. The organic phase is washed once withsaline (100 mL). The organic phase is concentrated under reducedpressure. MTBE (3×50 mL) is added and concentrated under reducedpressure to give the title compound.

Example 10 Latanoprost;(5Z)-(9CI)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoicAcid 1-methylethyl Ester (XVI)

Latanoprost acid (XV, EXAMPLE 9) is dissolved in DMF (10 mL) and addedto a slurry of cesium carbonate (1.6 g) in DMF (10 mL). 2-Iodopropane(0.49 mL) is added and the slurry is heated to 45° for about 6 hours.When the reaction is complete, MTBE (40 mL) and water (50 mL) are addedand the mixture is stirred for 15 minutes. The phases are separated andthe aqueous phase is washed with MTBE (20 mL). The organic phases arecombined and concentrated. The concentrate is chromatographed (silica,150 g, 230-400 mesh) eluting with MTBE. The appropriate fractions arepooled and concentrated to give the title compound.

Example 11 2-[(1R, 2R, 3R,5S)-3,5-Dihydroxy-2-[(3R)-3-hydroxy-1-octenyl]cyclopentyl]acetic Acid(XIX)

(−) Chlorodiisopinocampheylborane (27.0 g) is dissolved in THF (90 mL)and cooled to −35°. A mixture of[3aR-[3aα,4α(E),5β,6aπ]]-5-(benzoyloxy)hexahydro-4-(3-oxo-1-octenyl)-2H-cyclopenta[b]furan-2-one(XVII, J. Am. Chem. Soc., 96(18), 5865-76 (1974), 7.4 g) in THF (30 mL)is added maintaining the internal temperature of the mixture at <−35°.The mixture is stirred at −35 to −40° for 18 hours. Acetone (12.3 mL) isadded and the solution stirred at 20-25° for 2 hours. MTBE (50 mL) andsaturated aqueous sodium bicarbonate solution (50 mL) are added and thetwo-phase mixture is stirred for 5 min. The organic phase is separatedand washed once with water (50 mL), then concentrated under reducedpressure. The mixture is stirred at reflux with methanol (75 mL), water(7.5 mL) and potassium hydroxide (4.76 g) for 2 hours. The mixture isconcentrated under reduced pressure. The concentrate is partitionedbetween water (75 mL) and MTBE (75 mL). The aqueous phase is separatedand extracted with MTBE (2×50 mL). The pH of the aqueous phase isadjusted to about 1.2 with hydrochloric acid (3 M) and stirred for 2.5hours. The mixture is saturated with sodium chloride and then extractedwith MTBE (4×75 mL). The MTBE mixtures are combined and washed withsodium carbonate solution (1 M, 2×50 mL). The sodium carbonate solutionsare back extracted with MTBE (2×50 mL). The combined MTBE extracts areconcentrated to a volume of about 100 mL, then stirred for one hour witha solution of potassium hydroxide (3.29 g) in water (30 mL). The aqueousphase is separated and added to a slurry of anhydrous citric acid (9.68g) in ethyl acetate (100 mL). The phases are separated and the aqueousphase is extracted with ethyl acetate (4×50 mL). The combined ethylacetate extracts are filtered through anhydrous sodium sulfate (about 10g). The filtrate is concentrated under reduced pressure (30° maximumtemperature) to a volume of about 100 mL. Ethyl acetate (100 mL) isadded and the mixture is concentrated under reduced pressure (30°maximum temperature) to a volume of about 80 mL. The resulting slurry iscooled to −20° for one hour and then filtered, to give the titlecompound, mp=105-107°; NMR (d6-DMSO, 400 MHz) δ 5.37-5.49, 4.61, 4.58,4.06, 3.94, 3.76, 2.48, 2.35, 2.11-2.16, 1.8, 1.27-1.51 and 0.94; CMR(d6-DMSO, 100.6 MHz) δ 174.48, 136.33, 131.21, 75.65, 71.40, 69.37,53.79, 44.42, 44.31, 37.80, 31.82, 31.64, 25.16, 22.49 and 14.23.

Example 12(3aS,4S,5S,6aR)-Hexahydro-5-hydroxy-4-[(1E,3R)-3-hydroxy-1-octenyl]-2H-Cyclopenta[b]furan-2-one(XX)

2-[(1R, 2R, 3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-1-octenyl]cyclopentyl]acetic acid(XIX, EXAMPLE 11, 2.55 g) is stirred with MTBE (100 mL) andtrichloroacetic acid (0.102 g). The slurry is heated to reflux for morethan one hour. Then triethylamine (0.2 mL) is added. The mixture iscooled and washed once with water (50 mL) of water. The mixture is driedover anhydrous granular sodium sulfate and then concentrated underreduced pressure to give the title compound, NMR (CDCl₃, 400 MHz) δ5.58, 5.43, 4.88, 4.03, 3.92, 3.55, 2.8, 2.71, 2.3-2.5, 2.22, 1.9,1.2-1.6 and 0.89; CMR (CDCl₃, 100.6 MHz) δ 176.94, 136.79, 130.20,82.41, 76.27, 72.78, 56.12, 42.34, 39.61, 37.05, 33.98, 31.60, 25.06,22.52 and 13.94.

What is claimed is:
 1. A compound of the formula (VI)

where: (1) R₃ is —H and R₄ is —H, (2) R₃ is —H and R₄ is —O—CH₃ and (3)R₃ and R₄ are taken together to form a five member ring attached to the3- and 4-positions of the phenyl ring where the second ring from theR₃-position to the R₄-position is —CH═CH—O— and where . . . is a singleor double bond and pharmaceutically acceptable salts thereof.
 2. Acompound according to claim 1 where the cation of the salt is selectedfrom the group consisting of sodium, potassium, lithium, cesium,R₁R₂R₃N⁺—H where R₁, R₂ and R₃ are the same or different and are C₁-C₄alkyl, α-methylbenzylamine, pyridine, pyridine substituted with C₁-C₄alkyl, benzylamine and β-phenethylamine.
 3. A compound according toclaim 2 where the amine of the cation is triethylamine or pyridine.
 4. Acompound according to claim 1 where R₃ and R₄ are both —H and . . . is asingle bond which is 2-[(1R, 2R, 3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]aceticacid.
 5. A process for the preparation of a 15(S)-prostaglandinintermediate selected from the group consisting of compound (IV)

where: (1) R₃ is —H and R₄ is —H, (2) R₃ is —H and R₄ is —O—CH₃ and (3)R₃ and R₄ are taken together to form a five member ring attached to the3- and 4-positions of the phenyl ring where the second ring from theR₃-position to the R₄-position is —CH═CH—O—; where . . . is a single ordouble bond and where X₁₁ is phenyl or phenyl substituted with one thruthree C₁-C₄ alkyl, one thru three C₁-C₄ alkoxy, one phenyl, one thruthree —F, —Cl, —Br and —I and compound (XVIII)

where X₁₁ is defined above which comprises: (2) contacting a compoundselected from the group consisting of compound (III)

where R₃, R₄, X₁₁ and . . . are as defined above or compound (XVII),respectively,

where X₁₁ is defined above with (−)-chlorodiisopinocampheylborane whilemaintaining the reaction mixture temperature in the range of from about−50° to about 0° and (2) contacting the reaction mixture of step (1)with a boron complexing agent.
 6. A process according to claim 5 wherethe reaction mixture temperature is less than −20°.
 7. A processaccording to claim 6 where the reaction mixture temperature is fromabout −35 to about −45°.
 8. A process according to claim 5 where about 3to about 4 equivalents of (−)-chlorodiisopinocampheylborane are used. 9.A process according to claim 8 where at least 3.5 equivalents of(−)-chlorodiisopinocampheylborane are used.
 10. A process according toclaim 5 where prior to step (2), the reaction mixture of step (1) iscontacted with a readily reducible aldehyde or ketone.
 11. A processaccording to claim 10 where the readily reducible aldehyde or ketone isselected from the group consisting of C₁-C₆ aldehydes and ketones andbenzaldehyde.
 12. A process according to claim 11 where the readilyreducible aldehyde or ketone is acetone or methylethylketone.
 13. Aprocess according to claim 5 where the boron complexing agent isselected from the group consisting of water, C₁-C₆ alcohols and diols,ethanolamine, diethanolamine, triethanolamine and mixtures thereof. 14.A process according to claim 13 where the boron complexing agent isselected from the group consisting of water and diethanolamine.
 15. Aprocess according to claim 14 where the boron complexing agent is water.16. A process according to claim 15 where base is added with the boroncomplexing agent.
 17. A process according to claim 16 where the base isselected from the group consisting of carbonate, bicarbonate, mono- di-and tri-C₁-C₆ alkylamines, pyridine and pyridine substituted with C₁-C₄alkyl.
 18. A process according to claim 17 where the base is bicarbonateor carbonate.
 19. A process according to claim 5 where prior to, orafter, step (2), the reaction mixture is warmed to about 15 to about25°.
 20. A process according to claim 19 where the where the reactionmixture is warmed from about 1 to about 3 hr.
 21. A process according toclaim 5 where X₁₁ is phenyl.
 22. A process according to claim 5 wherethe 15(S)-prostaglandin intermediate is compound (IV)

known as[3aR-[3aα,4a(1E,3S*),5β,6aα]]-5-(benzoyloxy)hexahydro-4-(3-hydroxy-5-phenyl-1-pentenyl)-2H-cyclopenta[b]furan-2-one.23. A process according to claim 5 where the 15(S)-prostaglandinintermediate is compound (XVIII)

known as[3aR-[3aα,4α(E),5β,6aα]]-5-(benzoyloxy)hexahydro-4-(3-hydroxy-1-octenyl)-2H-cyclopenta[b]furan-2-one.